The COP9 signalosome is vital for timely repair of DNA double-strand breaks.
The COP9 signalosome is vital for timely repair of DNA double-strand breaks.
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COP9信号体对于及时修复DNA双链断裂至关重要。
DOI：
10.1093/nar/gkv270
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发表时间：
2015-05-19
影响因子：
14.9
通讯作者：
Shiloh Y
中科院分区：
文献类型：
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作者：
Meir M;Galanty Y;Kashani L;Blank M;Khosravi R;Fernández-Ávila MJ;Cruz-García A;Star A;Shochot L;Thomas Y;Garrett LJ;Chamovitz DA;Bodine DM;Kurz T;Huertas P;Ziv Y;Shiloh Y
DNA损伤反应被DNA双链断裂（DSB）强烈激活。DSB反应的主要动员剂是ATM蛋白激酶。我们发现COP 9信号体（CSN）是DSB反应和ATM靶点中的关键参与者。CSN是一种蛋白质复合物，通过从cullin支架上去除泛素样蛋白NEDD 8来调节cullin环泛素连接酶（CRL）复合物的活性。我们发现，CSN的物理招募DSB网站在neddylation依赖的方式，并需要及时修复DSB，影响两个主要的DSB修复途径之间的平衡-非同源末端连接和同源重组修复（HRR）。CSN对于深部末端切除的持续性是必不可少的-这是HRR的第一步。Cullin 4a（CUL 4A）以CSN和neddylation依赖的方式被募集到DSB位点，表明CSN在该途径中与CRL 4合作。此外，我们发现ATM介导的CSN亚基3在S410上的磷酸化对于正确的DSB修复是至关重要的，并且该磷酸化位点的丢失单独足以导致小鼠中的DDR缺陷表型。因此，DSB反应的这个新的分支显著影响基因组稳定性。
The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability.